WO1999048913A1 - Peptide turn mimetics - Google Patents

Peptide turn mimetics Download PDF

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Publication number
WO1999048913A1
WO1999048913A1 PCT/AU1999/000207 AU9900207W WO9948913A1 WO 1999048913 A1 WO1999048913 A1 WO 1999048913A1 AU 9900207 W AU9900207 W AU 9900207W WO 9948913 A1 WO9948913 A1 WO 9948913A1
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Prior art keywords
compounds
mimetics
group
converted
mimetic
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PCT/AU1999/000207
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English (en)
French (fr)
Inventor
Peter Joseph Cassidy
Peter Alan Hunt
Paul Francis Alewood
Tracie Elizabeth Ramsdale
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The University Of Queensland
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Application filed by The University Of Queensland filed Critical The University Of Queensland
Priority to EP99911522A priority Critical patent/EP1064300B1/en
Priority to DE69940500T priority patent/DE69940500D1/de
Priority to AU30193/99A priority patent/AU742747B2/en
Priority to JP2000537895A priority patent/JP4801257B2/ja
Priority to CA2325937A priority patent/CA2325937C/en
Publication of WO1999048913A1 publication Critical patent/WO1999048913A1/en
Priority to US12/386,988 priority patent/US20090275727A1/en
Priority to US12/858,954 priority patent/US20110040087A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • Peptide mimetics are used to reproduce the important structural and functional elements contained in a bio-active peptide sequence principally in order to develop novel pharmaceuticals with increased binding affinity, selectivity, stability and/or oral bioavailability compared to the bio-active peptide.
  • Reverse turns (beta and gamma turns and beta bul ⁇ ges ) are localised on the protein surface (Kuntz, 1972) and are of importance in protein interactions (Rose et al., 1985; Chalmers and Marshall, 1995) (and references contained therein).
  • reverse turns are important structures of peptide hormones and other biologically active peptides and cyclic peptides. (Giannis and Kolter, 1993; Olson et al., 1993; Kessler ef a/., 1995)
  • Peptide mimetics and peptide turn mimetics have as their object the replacement of a peptide sequence (a peptide turn) with a new compound which retains the elements essential for biological activity, thereby enabling or facilitating the development of novel pharmaceuticals devoid of the inherent problems of peptides - namely flexibility and poor pharmacodynamics.
  • the essential elements for biological activity are thought to be the peptide sidechain groups (Farmer and Ariens. 1982:
  • a peptide mimetic should include the side chain groups to have the best chance of retaining biological activity.
  • a peptide mimetic may then take the form of a framework for displaying sidechain groups in an appropriate arrangement.
  • the majority of reverse turns are beta turns.
  • the generally accepted definition of the beta turn is a sequence of four residues where the distance between the alpha carbons of residue (i) and residue (i+3) (defined as d) is less than 7 A, and the central residues (i+1 , i+2) are non- helical. (Lewis et al, 1973)
  • the general structure is shown below and includes the phi ( ⁇ ) and psi ( ⁇ ) backbone dihedral angles that are used to describe the conformation of the peptide backbone.
  • a schematic conversion of the beta turn to a beta turn mimetic is also shown - the peptide backbone is here replaced by an undefined framework
  • beta turn mimetics either do not provide for the incorporation of any sidechain functionality, or provide for a limited range of functionality, and at a limited number of positions.
  • the syntheses are often complex and lengthy, and most seriously may require a different synthetic method for different sidechain sequences (i.e. the synthetic method is not generic).
  • reverse turn mimetics and peptides or other compounds containing reverse turn mimetics
  • An important example of the application of reverse turn mimetics is the production of mimetics of known biologically active cyclic peptides (typically penta- or hexapeptides), as illustrated by Hirschmann and co-workers with D-D-giucose based mimetics. (Hirschmann et a/., 1992; Hirschmann et al., 1993)
  • beta turn mimetics having biological activity are known in the art.
  • U.S. Patent 4535169 discloses a method for the synthesis of beta turn mimetics which can incorporate a functional substitution for the (i+3) sidechain (only), and Krystenansky et al. disclose a leucine enkephalin mimetic based on this method which had analgesic activity one third the potency of morphine (Krstenansky et al, 1982).
  • the beta turn mimetics produced by these methods have ring sizes of twelve members and above.
  • Such large rings allow many conformations with d>7A, the mimetic conformations are therefore biased away from the accepted definition of a beta turn (d less than 7A), or more importantly the conformations are biased away from the most common reverse turn conformations which have d in the range of 4.5A to 6A (Rose et al, 1985; Gardner ef a/., 1993).
  • Enkephalin mimetics have been made (Gardner et al, 1993) and also mimetics of a loop of CD4 that inhibit binding of HIV gp120 and infection of human lymphocytes (Chen et al, 1992).
  • WO95/25120 that describes the use of turn mimetics in the synthesis of peptide vaccines for generating a protective immune response in warm blooded animals.
  • OBJECT OF THE INVENTION It is the object of the invention to provide novel compounds useful as, and useful for the synthesis of, conformationally constrained mimetics of biologically active peptides and proteins (peptide mimetics).
  • the invention provides new compounds and methods for the synthesis of new peptide reverse turn mimetics that can display a wide range of sidechain functions at all sidechain positions, can be incorporated in a peptide sequence, can be readily synthesised, and have a variety of conformations.
  • This invention describes novel compounds useful for the synthesis of peptide mimetics, and describes the use of these compounds 7 for the synthesis of novel reverse turn mimetics.
  • the reverse turn mimetics of the invention have the general structure X, or in a preferred embodiment the general structures l-VI (which are subsets of the general structure X; see below and Figures 1 and 2 on the attached sheets; the structures are fully described in the detailed description following this summary).
  • B-allyldialkylboranes e.g. Rg1a-i
  • allyl amines 4a-d are suprisingly valuable intermediates for the synthesis of new peptide mimetics, particularly reverse turn mimetics, enabling the synthesis of the significant variety of new reverse turn mimetics of the invention (having the general structure X), by the variety of different pathways described herein.
  • All the mimetic systems of the invention can be incorporated into peptide sequences (i.e. they include amino and carboxy termini in addition to the sidechain 8 functions), or if desired the amino and/or carboxy termini can be omitted from the mimetic.
  • the turn mimetics of the invention have a large variety of novel functionalised ring structures, each of these therefore having novel conformational characteristics. Furthermore, the structure and ring sizes of many of the turn mimetics make them well suited to the reproduction of the geometry of the more common native reverse turn conformations (those having d of 4.5A to 6A).
  • the synthetic methods described in this invention are generally superior to the prior art in terms of the capacity to include a wide range of side chain functions, in all the sidechain positions, without significant changes in the synthetic method; that is, the methods are more truly generic.
  • the control of chirality in the synthesis of the mimetics of the invention is superior to the prior art - an important consideration in the elucidation of structure-activity relationships and the development of novel pharmaceuticals, and other commercially useful peptide mimetics, as diastereomeric mixtures are normally unsuitable and may be impractical or impossible to separate on a commercial basis.
  • the invention includes all novel intermediates used in the preparation of the turn mimetics and more generally useful for the preparation of peptide mimetics, particularly 4-8(a-d), Scheme 1 and 10,
  • the peptide mimetics of this invention have the general structure X, shown below and defined as follows:-
  • R and R 2 and other R groups referred to hereinafter inclusive of R 1 , R 3 , R 4 , R n+3 and R n+4 etc. unless otherwise indicated, are amino acid side chain groups, each independently chosen and therefore the same or different (two separate R groups in the same mimetic do not require a different suffix to indicate that they are independently chosen and can be the same or different).
  • the definition of "amino acid side chain group” as used in this document is the same as the definition of "amino acid side chain moiety or derivative" as described in International Publication WO97/15577, pages 7-9 (Kahn, M), incorporated herein by reference.
  • Amino acid side chain groups typically correspond to, but are not limited to, those found in natural amino acids and derivatives and in common unnatural amino acids.
  • cyclic amino acid sidechains such as for proline, hydroxyproline and homoproline which involve a cyclization to the adjcent backbone nitrogen atom or the equivalent position, but only where this is possible (i.e. the amine or 10 equivalent atom is not already substituted as part of the heterocyclic mimetic framework).
  • Z is normally hydrogen, methyl, ethyl, formyl or acetyl, and may alternatively be R or -CH 2 R or -C(O)R where R is an amino acid side chain group, or alternatively Z is part of a cyclic amino acid side chain group joined to R 2 (for example to mimic a proline residue at position (i+1)).
  • R is an amino acid side chain group
  • Z is part of a cyclic amino acid side chain group joined to R 2 (for example to mimic a proline residue at position (i+1)).
  • ll(i) referred to hereinafter, Z cannot be hydrogen due to compound instability.
  • R c is the carboxy terminal part of the mimetic, typically - C(O)Pg c or alternatively hydrogen or an amino acid side chain group R or -CH 2 R.
  • Pg c (and Pg c' etc.) is a protecting group for carboxylic acid, typically including, but not limited to: alkoxy, benzyloxy, allyioxy, fluorenyl methyloxy, amines forming easily removable amides, or alternatively an appropriate cleavable linker to a solid phase support, or such a support itself, or alternatively hydroxy -OR, -NHR or remaining C-terminal portion of the mimetic system as described below.
  • carboxylic acid typically including, but not limited to: alkoxy, benzyloxy, allyioxy, fluorenyl methyloxy, amines forming easily removable amides, or alternatively an appropriate cleavable linker to a solid phase support, or such a support itself, or alternatively hydroxy -OR, -NHR or remaining C-terminal portion of the mimetic system as described below.
  • R N is the amino terminal part of the mimetic, i.e. -N(Z')Pg N , Z' is normally hydrogen, alternatively methyl (to mimic an N- methyl amino acid residue at position (i)), or alternatively part of a cyclic amino acid side chain group joined to R 1 (for example, to mimic a proline residue at position (i)).
  • Pg N (and Pg N ') is a protecting group for amine, typically including, but not limited to: Boc, Cbz, Fmoc, Alloc, trityl; or alternatively an appropriate cleavable linker to a solid phase support, or such a support itself, or alternatively hydrogen or R or -C(O)R where R is an amino acid side chain group, or alternatively part or all of the remaining N-terminal portion of the mimetic system, as described below.
  • M are normally hydrogen, alternatively one or more may be C- 1 -C 4 alkyl (preferred methyl), chloro, C- 1 -C4 alkoxy (preferred methoxy).
  • Q 1 Q can also be: -CH(R)CH 2 - or -CH 2 CH(R)CH 2 - or -CH 2 CH 2 CH(R)CH 2 - or - CH 2 CH(R)- or -CH 2 CH 2 CH(R)- or -CH(R)CH 2 CH 2 - or -
  • C(O)N(Q 5 )CH(R)Y- Q 5 is a covalent bond from the Q 4 group to the nitrogen atom in Q 3 (a cyclisation forming a bicyclic ring system).
  • Y is selected from the group consisting of C(O) and CH 2 and
  • Q 4 is selected from the group consisting of CHM 1 , C(O), CH(Q 5 )CH 2 and
  • the loop may also incorporate non-alpha amino acids, alpha dialkyl amino acids or any other amino acid which confers favourable properties on the mimetic system, for example increased binding affinity, or ease of detection, identification or purification.
  • the invention when used with such larger loops, is functioning as a covalent hydrogen bond mimic
  • Preferred embodiments of the invention are the structures I, as illustrated in Figures 1 and 2 and defined in Table 1 :-
  • Recursive entries of Q groups in Table 2 indicate a cyclisation - thus mimetics V and VI have a cyclisation between Q 1 and Q 2 , and mimetic IV has a cyclisation between Q 3 and Q 5 .
  • the groups Q 1 -Q 5 and Y are as defined above, and the other groups are asdefined herein.
  • the compounds of this invention have been designed to allow for incorporation in a peptide or protein chain, or for covalent attachment to any molecule or group that may be useful for the enhancement of the biological activity, or other property, of the peptide mimetic.
  • the mimetics typically contain amino and carboxy termini independent of the sidechain functions.
  • the term "remaining C- (or N-) 13 terminal portion of the mimetic” is any group, molecule, linker, support, peptide, protein, nucleoside, glycoside or combination of these, covalently linked to the mimetic. Typically such remaining portions would be peptides or combinations of peptides and other mimetics, or compounds to facilitate detection or identification, or to improve the pharmacodynamics or other useful feature of the mimetic system.
  • any R group (an amino acid side chain group) may serve as an attachment point to a solid support, or to a linker to a solid support, or as a covalent attachment point for another molecule that may be useful for the enhancement of the biological activity, or other property, of the mimetic, as described above for the remaining C- or N- terminal portions of the mimetic.
  • R 1 to R 4 is controlled by the use of chiral starting materials (L or D amino acids) and the avoidance of synthetic conditions which cause racemisation.
  • the configuration at chiral centres formed in the mimetic synthesis is dependent on several factors and can be controlled in several cases, but in other cases mixtures of diastereomers will result, which can potentially be separated by physical means.
  • a significant advantage of the invention is the superior level of chiral control possible at the chiral centres in the mimetics. 14
  • preparation of the imines 3 is completed by condensation of an amino acid aldehyde (compound 1) with an amine (2a-d).
  • the aldehydes 1 may be prepared by either oxidative procedures from the corresponding N-protected amino alcohol, or reduction of an N-protected amino acid derivative (Fehrentz and Lau, 1983), the different approaches have been reviewed, (Jurczak and Golebiowski, 1989) (see also Goel et al, 1988, Org. Syn. 67 69).
  • the amines 2a are amino acid esters (or other acid protected amino acid derivatives), which are commercially available or may be synthesised by standard procedures from amino acids.
  • Amines 2b-2d are prepared by reductive amination of an amine 2a and an amino acid aldehyde 1:
  • Amines 2d are prepared by repeated coupling/deprotection steps (as in conversion of 2b to 2c), standard techniques of peptide synthesis.
  • Coupled bonds Methods for the formation of amide bonds (coupling) are well established in the art.
  • the use of certain reagents for example those based on 1-hydroxy-7- azabenzotriazole (Ehrlich et al, 1993; Carpino et al, 1994), or the use of amino acid fluorides (Carpino et al, 1990; Wenschuh et al, 1994) is advantageous.
  • the example syntheses described in this document use solution phase chemistry.
  • the mimetics may also be synthesised by analogous solid phase techniques, or by a combination of solid phase and solution phase techniques, or the mimetics may be incorporated in normal solid phase peptide synthesis in the same way as a standard protected amino acid derivative.
  • Fr ⁇ chtel and Jung Fr ⁇ chtel and Jung (Fr ⁇ chtel and Jung, 1996) details the state of the art in solid phase organic synthesis (in 1996).
  • the imines 3 form rapidly at room temperature on mixing of the amine and aldehyde in an appropriate solvent, e.g. CH CI 2 or diethyl ether, with liberation of water.
  • an appropriate solvent e.g. CH CI 2 or diethyl ether
  • the water is removed with a drying agent, e.g. dried MgSO 4 , which is subsequently removed by filtration.
  • the imines are then reacted with an allyl metal reagent (Rg1) to give, after work-up, compounds 4 (Scheme 1).
  • allyl organometals such as allyl magnesium bromide
  • imines 3 are unsuitable for reaction with imines 3 due to a lack of selectivity for the imine function over the carboxylic acid derived groups (esters, amides) also present in 3.
  • Allyl copper and zinc reagents have been used in selective reactions with imines (Bocoum et al., 1991 ; Basile et al., 1994) but in the case of imines 3 these reagents 19 result in extensive racemisation at the D-imine chiral centre, and attack esters present in the imine to a significant extent.
  • reaction product typically contains a mixture of four diastereomers and also by-products from reaction at the carboxylic acid derived groups (especially esters).
  • reaction of the imines 3 with allyl boranes such as B-allyl-9- borabicyclo[3.3.1]nonane (allyl-9-BBN), Rg1a, gives excellent results and reasonable diastereoselectivity (>50% isolated yield based on crude aldehyde, and ⁇ 80:20 diastereoselectivity where R is not H).
  • allyl trialkylboranes with appropriate chiral alkyl groups such as B-allyl-diisopinocampheylborane (allyl-DIP, Rg1b and Rg1c), or the diisocaranylboranes Rg1d-e it is possible to produce give only the major product (one diastereomer, >99:1 ) in good yield and purity.
  • the configuration at the new stereocentre was determined to be (R) when using aldehyde derived from natural (S) configuration amino acids, and the stereocontrol exerted by the D-aldehyde chiral centre was dominant over the effect of chiral boron ligands and over the effect of the other amino acid chirality in all cases examined.
  • the (+)DIP reagent Rg1b gave higher diastereoselectivity on imines derived from natural (S) configuration aldehydes than Rg1c (from (-)DIP).
  • the purity of the allylation products 4a may also be improved by the removal of the ester protecting group Pg c to give a crystalline amino acid which can be recrystallised (e.g. from ethanol/water) to the desired level of purity and then reprotected. 20
  • crotyl Rg1f, Rg1h-i
  • methallyl Rg1g
  • other substituted allyl derivatives leads to bridge substituted mimetics (mimetics where at least one of M, M' and M" is not hydrogen) with further opportunities for stereocontrol.
  • the less reactive allyl boronate allyldimethoxyboron Rg1j was found to give inferior results (significant epimerisation at CD(i)) compared to the allyltrialkylboranes.
  • Many allylboronate and related reagents e.g. Rg1k-m are described in the literature, and some of these may be more effective than allyldimethoxyboron for the conversion of 3 to 4.
  • the imines 3 formed from two non-glycine derivatives are significantly hindered about the imine nitrogen, and the use of bulky boron ligands (such as diisopinocampheyl) can reduce the reaction yield.
  • bulky boron ligands such as diisopinocampheyl
  • smaller chiral B-allyl compounds e.g. those based on 2,5- dimethylboracyclopentane are preferred (e.g. Rg1n, Figure 3). 21
  • acids 6 can be synthesised directly by oxidative cleavage of the alkenes 5, e.g. by RuCI 3 /NalO 4 ; aldehydes/ketones 8 may be synthesised directly from 5 by ozonolysis (for oxidation methods see for example the monograph by Hudlicky (Hudlicky) and references therein), but this process is not sufficiently selective and results in over-oxidation and the formation of other by-products.
  • the cis aldehydes can also be isomerised to the trans by treatment with catalytic acid, e.g. HCI in CHCI 3 .
  • oxidation reagents may effect this conversion, e.g. pyridinium dichromate.
  • Glycols 7 may also be oxidised directly to acids, e.g. by RuCl 3 /NalO 4 .
  • carboxylic acids 6 can be converted to aldehydes by the same general methods used for the formation of protected ⁇ -amino aldehydes described above. (Jurczak and Golebiowski, 1989).
  • the carboxylic acid can be selectively reduced to the alcohol in the presence of carboxylic esters by the use of borane (Brown and Krishnamurthy, 1979), then oxidised to the aldehyde as previously described. (Jurczak and Golebiowski, 1989)
  • the epoxides 29 alkylate amines 9 on warming in ethanol or DMSO solution to give the amino alcohols 30.
  • the alcohol may then be oxidised to the ketone 32 by the use of TPAP (tetrapropylammonium perruthenate) with N- methylmorpholine-N-oxide in CH 2 CI 2 /acetonitrile by the method of Griffith and Ley (Griffith and Ley ,1990).
  • VI are accomplished from the corresponding D-turn mimetic systems S, where the R 1 side chain group is derived from an aspartic acid (V) or glutamic acid (VI) derivative.
  • alkylated aspartic and glutamic acid derivatives 1d and 1e the alkylated derivatives 39-42 can be prepared by a number of methods known in the art. Selected methods are summarised in Schemes 16 and 17. Rapoport and co-workers have developed methods for the selective alkylation of N-phenylfluorenyl protected aspartic and glutamic acid derivatives (Koskinen and Rapoport, 1989; Wolf and Rapoport, 1989). A review by Sardina and Rapoport, and references contained therein, describe several methods for the synthesis of alkylated aspartic and glutamic acid derivatives, incorporated herein by 27 reference (Sardina and Rapoport. 1996). Derivatives 39-42 are converted to aldehydes 1d and 1e by the methods previously described for for the preparation of aldehydes 1.
  • aminoketones 51 can be acylated with an amino acid fluoride 15 to give compounds 53 which can be deprotected and cyclised (by reductive amination) by hydrogenation in mild acid conditions (H 2 /Pd-C, 0.1M HCI in EtOH).
  • the reductive amination-cyclisation is diastereoselective, only one diastereomer of the mimetics l(i)a were formed from 53, with the configuration at the new stereocentre controlled by the R 2 stereocentre.
  • the amide 56 was synthesised from commercially available
  • Boc-Tyrosine(OBn)OH by coupling with N,O-dimethylhydroxylamine hydrochloride, 1 equivalent, in DMF/CH 2 CI 2 (1 :5) using HBTU reagent (1 eq.) and DIEA (2 eq.) at room temperature.
  • the CH 2 CI 2 was evaporated in vacuo and the residue partitioned between diethyl ether and aq.
  • the aldehyde 57 was prepared by the method of Fehrentz and Castro (Fehrentz and Castro, 1983) as follows: to a stirred solution of 4.2 g of amide 56 in 100 mis of anhydrous diethylether cooled to 0°C was added 0.51 g lithium aluminium hydride. After 10 minutes a solution of 1.5g NaHSO 4 in 30 mis of water was added. The reaction mixture was diluted with more ether and washed with 1M HCI, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulphate. The volatiles were removed under reduced pressure to give a waxy solid which was recrystallised from cold ether/hexane to give 2.6 g (72%) of 57 as a white solid.
  • the imine 58 was formed by the reaction of the aldehyde 57
  • the amine 59 (930 mg, 1.7 mmol) was dissolved in ethyl acetate (15 mL) and 37% aq. formaldehyde solution added (1 mL). The solution was stirred vigorously at room temperature for 1 h (or until the reaction was complete) and then diluted with ether (100 mL) and washed in turn with aq. NaHCO 3 , water (x3), brine and then dried (MgS ⁇ 4).
  • CDCI 3 D DD(peaks due to the carbamate rotamers are placed in parentheses, major rotamer first) 169.8 (ester); 157.2 (tyrosine O-ipso)
  • NMO N-methylmorpholine- N-oxide
  • the imidazolidine ring of 65 was deprotected with a solution of acetic acid-methanol-water (-1 :1:1 , stirred as a very dilute solution for several days then lyophilised) to give crude 66 as a white amorphous solid.
  • Mass Spectrum (ISMS) m/z 601 (M+H + ), calculated for C 35 H 4 4N 4 O 5 : 600.
  • Example (B) Synthesis of a (4,5)-cis imidazolidine aldehyde by oxidation of a diol.
  • the diol 67 prepared from alkene 60 (as described above) (1mmol) was dissolved in THF (10 mL) and H 5 IO 6 (1 mmol) 36 dissolved in THF (-20 mL) was added and the reaction stirred at room temperature. A precipitate of iodic acid rapidly formed and the reaction was complete in ⁇ 5 min.
  • the THF solution was diluted with ether and washed in turn with 10% aq.Na 2 CO 3 , water, brine and then dried (MgSO 4 ).
  • the product aldehyde 68 was formed in good yield and purity.
  • Boc-glycine was coupled with N,O-dimethyl hydroxylamine hydrochloride, 1 equivalent, in DMF/CH 2 CI 2 (1 :5) using HBTU reagent (1 eq.) and DIEA (2 eq.) at room temperature.
  • the CH 2 CI 2 was evaporated in vacuo and the residue partitioned between diethyl ether and aq. NaHCO 3 .
  • the aqueous layer was separated and the ether layer washed in turn with 1M HCI (x2), aq. NaHCO 3 , brine, and then dried over MgSO4.
  • CDCI 3 D 194.9 ketone; 155.8 carbamate; 133.6 vinyl; 129.6 vinyl;
  • the amine 71 was protected as the benzyl carbamate by standard procedures as follows: the crude amine product 71 (1.68 g, -5 mmol) was dissolved in ethyl acetate (30 mL) to which was added a solution of KHCO 3 (1.2 g) in water (15 mL). This mixture was vigorously stirred and cooled in an ice bath and to it was added benzyl chloroformate (780 uL of a 95% solution, 5.2 mmol) dropwise over 5 min. The reaction was stirred for a further 15 min then allowed to warm to room temperature with stirring for an additional 2 h.
  • the mixture of epimeric amines 73 (260 mg, 0.4 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon added (100 41 mg). The solution was hydrogenated (40 psi H 2 ) at room temperature for
  • Example (D) Selective synthesis of the 3(S), 5(S) diastereomer 75 by the short method
  • the 3(S)5(S) diastereomer, the minor product formed as described above, can be selectively synthesised by the use of an intramolecular reductive amination-cyclisation as described below:
  • Z-phenylalanine acid fluoride was prepared by general literature methods (Carpino et al, 1990; Wenschuh et al, 1994) as follows: 1.1 equivalents of diethylaminosulfurtrifluoride (DAST) were added to ZPheOH in dry dichloromethane solution under nitrogen at 0°C. After stirring for 15 min the reaction was worked up by pouring onto iced water and separating the organic layer, washing once with cold water and then drying over MgSO 4 . The product was purified by precipitation from ether/petroleum ether and dried in vacuo.
  • DAST diethylaminosulfurtrifluoride
  • the solution was hydrogenated at 30 psi H 2 (room temperature) for 8 h and then diluted with aq. NaHCO 3 and extracted with ethyl acetate. The organic layer was washed with water (x2) and then brine then dried over
  • CDCI 3 D 173.9; 172.0; 138.9; 135.9; 128.7, 128.4, 128.0, 126.3: Ar;
  • the amine 81 (50 mg, 0.06 mmol) in THF (0.6 mL) was cooled in a dry ice acetone bath and ammonia gas added until -30 mL of ammonia had condensed. Small pieces of sodium metal (3-6 mg) were added until the blue colour persisted. The reaction was quenched by the addition of ammonium carbonate (25 mg), the dry ice bath removed and the solvent allowed to evaporate at room temperature.
  • the amine 81 was dissolved in CH 2 CI 2 /CF 3 CO 2 H (2ml, 1 :1 ) and stirred at room temperature for 30 minutes after which the Boc group had been removed. 10ml of CH 2 CI 2 was then added and the volatiles removed in vacuo (repeat once). The residue was again dissolved in CH 2 CI 2 and acetic anhydride (2 eq.) added along with diisopropylethylamine (DIEA, 5 eq.), and the reaction stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue dissolved in ethyl acetate and washed with aq. NaHCO 3 then brine and then dried over MgSO 4 .
  • Compound 84 was prepared from 83 by dissolving metal reduction as described for the preparation of 82 above. Purification was carried out by HPLC under the same conditions as for 82. Testing of Aro-Glv-Asp mimetics 82 and 84 for inhibition of platelet aggregation in human platelet rich plasma (PRP) 48
  • the peptide sequence arginine-glycine-aspartic acid is important to the binding of proteins to certain integrin receptors, such as the GP
  • integrin receptors such as the GP
  • GPnb-nia antagonists have therapeutic potential as anti- thrombotics, there are several in early clinical trials(Humphries, Doyle et al, 1994). Mimetics based on D-turn structures centred on the Asp residue have been successful, this structure was chosen to test the compounds of the invention.
  • Bocphenylalanine N,O-dimethylhydroxylamide 85 was synthesised by the general solution phase coupling procedure as previously described from Boc-phenylalanine and N,O-dimethyl hydroxylamine hydrochloride. Yield: -quantitative. Purification: on a short silica column eluting with ether.
  • the amide 85 was reduced to Bocphenylalanine aldehyde 86 by the method of Fehrentz and Castro (Fehrentz and Castro, 1983) Briefly: amide (2 mmol) dissolved in dry ether (20 mL) and cooled and in 50 an ice bath under nitrogen, then LiAIH 4 (95 mg, 2.5 mmol) added and stirring continued 15 min. Then KHSO 4 (477 mg, 3.5 mmol) in 10 mL water added and then 150 mL ether and wash with 1 M HCI (cold) (x3), aq. NaHCO 3 , brine, and dried over MgSO 4 .
  • Methyl leucinate hydrochloride (0.80 g, 4.4 mmol) was neutralised with 10% aq. Na 2 CO 3 solution (25 mL), and the solution was mixed with brine (25 mL) and extracted with CH 2 CI 2 (3x20 mL). The organic extracts were dried over MgSO 4 and most of the solvent removed under vacuum (-2 mL residue).
  • This solution of methyl leucinate was added to Boc phenylalanine aldehyde 86 (1.1 g, 4.4 mmol) in CH 2 CI 2 (5 mL), the stirred solution soon became turbid due to the separation of water, dried MgSO 4 (500 mg) was added and the solution cleared.
  • B-allyl-9-borabicyclononane Rg1a can be synthesised from B-methoxy-9-borabicyclononane (synthesised in turn from the methanolysis of 9-BBN (Kramer and Brown, 1974)) by the method of Kramer (Kramer and Brown, 1977).
  • 9-BBN crystalline dimer, 8.97 g, 73.5 mmol
  • anhydrous ether 75 mL
  • the solution was estimated by reaction with a known amount of methylphenylketone in ether (found to be -0.57M, equal to 78% yield).
  • the clear solution of B-allyl-9-BBN was used directly for allylation of the imines. (This procedure was adapted from one described by Rachlera and Brown (Racheria et al, 1992))
  • the imine 87 (-23 mmol) was dissolved in dry diethylether (100 mL) under nitrogen and the stirred solution cooled to -78°C.
  • the amino acid 89 was esterified to 90 by the method of Bodansky and Bodansky (Bodansky and Bodansky, 1984) as follows: the amino acid 89 (400 mg, 1 mmol) was dissolved in methanol/water and neutralised with Cs 2 CO 3 (300 mg), then the solvents were removed in vacuo, then DMF added and removed in vacuo. The residue was dissolved in DMF (10 mL) and benzyl bromide (190 mg, 1.1 mmol, purified by passage through a short column of basic alumina) added to the stirred solution. After 2 h the reaction was diluted with aq. NaHCO 3 and extracted with 1 :1 EtOA light pet.
  • the amine 90 (500 mg, 1 mmol) was dissolved in ethyl acetate (20 mL) and 37% aqueous formaldehyde solution (0.5 mL) was added. The solution was stirred for 12 h and then diluted with light 54 petroleum (40 mL) and washed in turn with aq. NaHCO 3 , water (x2) and brine and then dried (MgSO 4 ). Removal of the solvent in vacuo gave the product 91 as a clear oil in approximately quantitative yield. Further purification was carried out by flash chromatography eluting with 10% ethyl acetate in light pet.
  • the glycol 92 (87 mg, 0.16 mmol) was dissolved in THF (4 mL) and H 5 IO 6 (37 mg, 0.16 mmol) dissolved in THF (3 mL) was added 55 and the reaction stirred at room temperature. A precipitate of iodic acid rapidly formed and the reaction was complete in ⁇ 5 min.
  • the THF solution was diluted with ether and washed in turn with 10% aq.Na 2 CO 3 , water, brine and then dried (MgSO 4 ).
  • the product aldehyde 93 was of good purity but was not particularly stable to storage. Any traces of acid must be rigorously excluded to prevent isomerisation to the trans isomer.
  • R CH 2 CH(C H 3 ) 2
  • the aldehyde 93 (50 mg, 0.1 mmol) was dissolved in 1 ,2- dichloroethane (5 mL) and alanine methyl ester (-2 equivalents) and acetic acid (1drop, -14 mg) were added. The mixture was stirred at room temperature for 5 min and then NaBH(OAc) 3 (40 mg, 2 eq.) was added and stirring continued for 30 min. The solvent was then removed in vacuo and the residue partitioned between EtOAc and 10% aq. Na 2 CO 3 , the organic layer was washed with water and brine and then dried (MgSO 4 ). The product contained both diastereomers in the ratio -9:1 , transxis.
  • D-turn mimetic compounds 96 and 97 as described below:
  • the solution was filtered and the solvent removed in vacuo, then the residue was dissolved in DMF (2 mL) and diluted with CH 2 CI (15 mL) and DIEA (50 mg, -0.4 mmol) and BOP reagent (50 mg, 0.11 mmol) were added to the stirred solution at room temperature.
  • the trans (4(S)) aldehyde was obtained by the acid catalysed isomerisation of the cis diastereomer 93 in chloroform solution with catalytic HCI present. Significant decomposition to multiple unidentified by-products (most having high Rf) also occurs under the isomerisation conditions.
  • the product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether for a yield of about 35% 98 from crude 93.
  • 1 H NMR 300 MHz, CD 3 CN, ref.
  • Compound 70 was prepared as described above, and reacted with alanine methyl ester to form 99 using the same method previously described for the synthesis of 71.
  • the crude amino ketone 99 (1.22g) was reacted with Cbz-glycine symmetric anhydride (synthesised from 1.95g CbzGlyOH and 9.3mls 0.5M dicyclohexylcarbodiimide in dichloromethane) and 0.6g DIEA in dichloromethane.
  • the catalyst was filtered off (celite) and the solvent removed under reduced pressure, the residue was then treated with tetrabutylammonium fluoride in THF to remove the FMOC group.
  • the free amine was then reprotected by addition of benzyl chloroformate (65 mgs) and DIEA (100 mgs). After stirring for 1 hour ethyl acetate was added and the organic layer was washed with 1 M HCI, water, then brine, dried over magnesium sulfate (removed by filtration) and the volatiles removed under reduced pressure to leave an oil which was purified by flash chromatography eluting with 3-5% ethanol in chloroform for a yield of about 40% of 105 based on 103.
  • BocHN X >- BocHN Af ⁇ > ⁇ B OC HN' ⁇ T ⁇
  • the amino ketone A4 (690 mg, 2 mmol) was then coupled with Z-alanine to give A5 using standard solution phase coupling procedure with HBTU reagent and DIEA in CH 2 CI 2 /THF.
  • oxidise e.g. dihydroxylate 5a-d RuCl 3 , NaI0 4
  • R 3 couple R 1 M fi o CT P g C

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  • Genetics & Genomics (AREA)
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AU30193/99A AU742747B2 (en) 1998-03-24 1999-03-24 Peptide turn mimetics
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US7964181B2 (en) 2006-03-30 2011-06-21 Palatin Technologies, Inc. Amino acid surrogates for peptidic constructs
US8114844B2 (en) 2006-03-30 2012-02-14 Palatin Technologies, Inc. Linear and cyclic melanocortin receptor-specific peptidomimetics
JP2012140400A (ja) * 1999-10-04 2012-07-26 Tranzyme Pharma Inc 創薬に有用な大環状化合物ライブラリーのコンビナトリアル合成
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013878A2 (en) * 1991-02-07 1992-08-20 Board Of Trustees Of The University Of Illinois Conformationally restricted mimetics of beta turns and beta bulges and peptides containing the same
WO1995025120A1 (en) * 1994-03-15 1995-09-21 Molecumetics, Ltd. Peptide vaccines and methods relating thereto
WO1996022304A1 (en) * 1995-01-20 1996-07-25 Molecumetics, Ltd. Conformationally constrained reverse-turn library and methods relating thereto
WO1997015577A1 (en) * 1995-10-27 1997-05-01 Molecumetics Ltd. Reverse-turn mimetics and methods relating thereto
WO1998049168A1 (en) * 1997-04-30 1998-11-05 Molecumetics Ltd. Reverse-turn mimetics and methods relating thereto

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090275727A1 (en) * 1998-03-24 2009-11-05 Mimetica Pty Limited Peptide turn mimetics

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013878A2 (en) * 1991-02-07 1992-08-20 Board Of Trustees Of The University Of Illinois Conformationally restricted mimetics of beta turns and beta bulges and peptides containing the same
WO1995025120A1 (en) * 1994-03-15 1995-09-21 Molecumetics, Ltd. Peptide vaccines and methods relating thereto
WO1996022304A1 (en) * 1995-01-20 1996-07-25 Molecumetics, Ltd. Conformationally constrained reverse-turn library and methods relating thereto
WO1997015577A1 (en) * 1995-10-27 1997-05-01 Molecumetics Ltd. Reverse-turn mimetics and methods relating thereto
WO1998049168A1 (en) * 1997-04-30 1998-11-05 Molecumetics Ltd. Reverse-turn mimetics and methods relating thereto

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CALLAHAN J F, ET AL.: "THE USE OF GAMMA-TURN MIMETICS TO DEFINE PEPTIDE SECONDARY STRUCTURE", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 49, no. 17, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 3479 - 3488, XP000979569, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(01)90208-X *
EGNER U, MUELLER-FAHRNOW A, ECKLE E: "TURN MIMETICS FOR PEPTIDE DESIGN", PESTICIDE SCIENCE., ELSEVIER APPLIED SCIENCE PUBLISHER. BARKING., GB, vol. 51, 1 January 1997 (1997-01-01), GB, pages 95 - 99, XP000979573, ISSN: 0031-613X, DOI: 10.1002/(SICI)1096-9063(199709)51:1<95::AID-PS609>3.0.CO;2-3 *
FAIRLIE D P, WEST M L, WONG A K: "TOWARDS PROTEIN SURFACE MIMETICS", CURRENT MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS, NL, vol. 05, no. 01, 1 February 1998 (1998-02-01), NL, pages 29 - 62, XP000987330, ISSN: 0929-8673 *
GARDNER B, NAKANISHI H, KAHN M: "CONFORMATIONALLY CONSTRAINED NONPEPTIDE BETA - TURN MIMETICS OF ENKEPHALIN", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 49, no. 17, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 3433 - 3448, XP000979568, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(01)90205-4 *
HANESSIAN, S. MCNAUGHTON-SMITH, G. LOMBART, H.-G. LUBELL, W.D.: "Design and Synthesis of Conformationally Constrained Amino Acids as Versatile Scaffolds and Peptide Mimetics", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 53, no. 38, 22 September 1997 (1997-09-22), AMSTERDAM, NL, pages 12789 - 12854, XP004106190, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(97)00476-6 *
KAHN M: "PEPTIDE SECONDARY STRUCTURE MIMETICS: RECENT ADVANCES AND FUTURE CHALLENGES", SYNLETT, GEORG THIEME VERLAG, DE, 1 November 1993 (1993-11-01), DE, pages 821 - 826, XP000979574, ISSN: 0936-5214, DOI: 10.1055/s-1993-22619 *
RIPKA W C, ET AL.: "PROTEIN BETA-TURN MIMETICS I.DESIGN, SYNTHESIS, AND EVALUATION IN MODEL CYCLIC PEPTIDES", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 49, no. 17, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 3593 - 3608, XP000979570, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(01)90217-0 *
RIPKA W C, ET AL.: "PROTEIN BETA-TURN MIMETICS II: DESIGN, SYNTHESIS, AND EVALUATION IN THE CYCLIC PEPTIDE GRAMICIDIN S", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 49, no. 17, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 3609 - 3628, XP000979571, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(01)90218-2 *
SATO M, ET AL.: "DESIGN AND SYNTHESIS OF HYPERTREHALOSEMIC HORMONE MIMETICS", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 03, no. 06, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 1277 - 1282, XP000982937, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(00)80331-5 *
SU T, ET AL.: "NONPEPTIDE BETA-TURN MIMETICS OF ENKEPHALIN", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 03, no. 05, 1 January 1993 (1993-01-01), AMSTERDAM, NL, pages 835 - 840, XP000982938, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(00)80676-9 *

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FR2803594A1 (fr) * 2000-01-11 2001-07-13 Centre Nat Rech Scient Oligomeres de mimes contraints non peptidiques de dipeptides ou de tripeptides, et leurs utilisations
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